All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

Susan L Bellis

Candace L Floyd

Richard B Marchase

Michelle L Olsen

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

O-GlcNAcylation is a dynamic protein posttranslational modification that adds the monosaccharide ß-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues on nucleocytoplasmic proteins. The hippocampus is a part of brain that has been shown to play a crucial role in learning and memory. Hippocampal neurons have high expression of O-GlcNAc transferase and O-GlcNAcase, which catalyze the addition and removal of GlcNAc from proteins respectively. Moreover, synaptic plasticity which is the strengthening or weakening of synaptic function on short- and long-term time scales is believed to be a cellular correlate of learning and memory. Several forms of synaptic plasticity have been characterized in the Schaffer collateral pathway, the connection of the CA3 neurons to the CA1 dendrite. Synaptic function is highly regulated by serine and threonine phosphorylation of the same residues potentially subjected to O-GlcNAcylation. The role of protein O-GlcNAcylation in synaptic transmission and the effect the post-translational modification may have on the expression of long-term potentiation and long-term depression is not known. Due to the expression of OGT and O-GlcNAcase in CA3 and CA1 neurons, the process of O-GlcNAcylation may have a role in the overall processes of learning and memory. Thus in this study, we tested whether increased protein O-GlcNAcylation can affect synaptic transmission, synaptic plasticity and hippocampal-dependent learning. In dendritic field recordings in CA3-CA1 hippocampal neurons, we find that increasing protein O-GlcNAcylation induced long term depression, a form of synaptic plasticity. In addition, we find that the depression is saturatable and reversible suggesting a physiological role for O-GlcNAcylation in synaptic function. Furthermore, we found that the GluA2, but not the GluA1, subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor was O-GlcNAc modified. These results suggest that O-GlcNAcylation of GluA2 may contribute to the depression induced by increasing protein O-GlcNAcylation. We also found that increasing protein O-GlcNAcylation in vivo impairs novel object recognition but has no effect on mobility or anxiety. Together, these data support the notion that protein O-GlcNAcylation plays a role in hippocampal transmission, plasticity, and behavior.

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